# NM_003002.4(SDHD):c.65G>C (p.Arg22Pro)

https://sugi.bio/variant/sdhd-p-arg22pro

## Summary

**SDHD p.Arg22Pro (c.65G>C)** is classified **Uncertain significance** in SDHD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1092); Absent from gnomAD v4.1; Associated with pheochromocytoma.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1555186772 · 2 submitters · 4 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SDHD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to pheochromocytoma.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 121 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015105/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SDHD](https://sugi.bio/atlas/gene/SDHD/) |
| Protein change (HGVS p.) | p.Arg22Pro |
| Coding change (HGVS c.) | c.65G>C |
| MANE Select transcript | [NM_003002](https://www.ncbi.nlm.nih.gov/nuccore/NM_003002) |
| dbSNP | [rs1555186772](https://www.ncbi.nlm.nih.gov/snp/rs1555186772/) |
| Variant type | single nucleotide variant |
| Location | chr11:112087869-112087869 (GRCh38) |
| ClinVar | [VCV1923670](https://www.ncbi.nlm.nih.gov/clinvar/variation/1923670/) |

**All HGVS expressions:** `LRG_9:g.6023G>C`, `LRG_9t1:c.65G>C`, `NC_000011.10:g.112087869G>C`, `NC_000011.9:g.111958593G>C`, `NG_012337.3:g.6023G>C`, `NG_033145.1:g.3930C>G`, `NG_123945.1:g.133G>C`, `NM_001276503.2:c.65G>C`, `NM_001276504.2:c.52+910G>C`, `NM_001276506.2:c.65G>C`, `NM_003002.2:c.65G>C`, `NM_003002.4:c.65G>C`, `NR_077060.2:n.100G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1092)
- REVEL 0.529 (indeterminate)
- SaProt LLR -8.451 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 0.897, GERP -1.98, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 17.91**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.83** across the covering region of the MANE Select transcript (112,086,908–112,094,967), spanning 8,059 bp. Chi-square p 0.019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.30 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.21** (loss), gain 0.02 / loss 0.21. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SDHD** population constraint: LOEUF 0.581, pLI 0.90513, missense-Z 0.80794; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Limited (AR)
- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.50, 63% of residues very-high.

**2 experimental structure(s)** (PDB): [8GS8](https://www.rcsb.org/structure/8GS8), [9KC4](https://www.rcsb.org/structure/9KC4).

## What this gene does {#gene-function}

*Describes the biological roles of SDHD (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

SDHD participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Maturation of TCA enzymes and regulation of TCA cycle](https://reactome.org/content/detail/R-HSA-9854311) | curated |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** tricarboxylic acid cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-22.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-20 |

## Associated conditions {#conditions}

[pheochromocytoma](https://sugi.bio/atlas/disease/pheochromocytoma/), [Carney-Stratakis syndrome](https://sugi.bio/atlas/disease/carney-stratakis-syndrome/), [Cowden syndrome 3](https://sugi.bio/atlas/disease/cowden-syndrome-3/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Pheochromocytoma, Carney-Stratakis syndrome, Cowden syndrome 3, Paragangliomas with sensorineural hearing loss, Hereditary cancer-predisposing syndrome, MAX-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, PARAGANGLIOMA AND GASTROINTESTINAL STROMAL TUMOR, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **22** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SDHD p.Arg22Ter](/variant/sdhd-p-arg22ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SDHD variant pages (same residue, condition, or type): [SDHD p.Arg22Ter](/variant/sdhd-p-arg22ter), [SDHD p.Arg22Gln](/variant/sdhd-p-arg22gln), [SDHD p.Arg22=](/variant/sdhd-p-arg22), [SDHD c.170-1G>T](/variant/sdhd-c-170-minus-1g-t), [SDHD c.170-2A>G](/variant/sdhd-c-170-minus-2a-g), [SDHD c.314+1G>A](/variant/sdhd-c-314-plus-1g-a), [SDHD c.314+1G>T](/variant/sdhd-c-314-plus-1g-t), [SDHD c.315-1G>A](/variant/sdhd-c-315-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1923670). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*